Germ warfare: the new generation of drugs that could blast any viral disease

This article was taken from the May 2012 issue of Wired
magazine. Be the first to read Wired's articles in print before
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There's a moment in the history of medicine that's so
cinematic it's a wonder no one has put it in a Hollywood film. The scene is a London laboratory in
1928. Alexander Fleming, a Scottish microbiologist, is back from a
holiday and is cleaning up his work space. He notices that a speck
of mould has invaded one of his cultures of Staphylococcus
bacteria. But it isn't just spreading through the culture. It's
killing the bacteria surrounding it.

Fleming rescued the culture and carefully isolated the mould. He
ran a series of experiments confirming that it was producing a
Staphylococcus-killing molecule. Then he discovered that the mould
could kill many other species of infectious bacteria as well. "I
had a clue that here was something good, but I could not possibly
know how good it was," he later said.

No one at the time could have known how good penicillin was.
In 1928, even a minor wound was a potential death sentence, because
doctors were mostly helpless to stop bacterial infections. Through
his investigations into that peculiar mould, Fleming became the
first scientist to discover an antibiotic -- an innovation that
would eventually win him the Nobel Prize. Penicillin saved countless lives, killing off
pathogens from staph to syphilis but causing few side effects. His
work led other scientists to seek out and identify more
antibiotics, which helped to change the rules of medicine. Doctors
could prescribe drugs that effectively wiped out most bacteria,
without even knowing what kind of bacteria were making their
patients ill.

Of course, even if bacterial infections were totally eliminated,
we would still get sick. Viruses -- which cause their own panoply
of diseases, from the common cold and the flu to Aids and Ebola --
are profoundly different from bacteria, so they don't present the
same targets for a drug to hit. Penicillin interferes with the
growth of bacterial cell walls, for example, but viruses aren't
even cells -- they're just genes packed into "shells" made of
protein. Other antibiotics, such as streptomycin, attack bacterial
ribosomes, the protein-making factories inside the pathogens. A
virus doesn't have ribosomes; it hijacks the ribosomes inside its
host cell to make the proteins it needs.

We do currently have "antiviral" drugs, but they're a pale
shadow of their bacteria-fighting counterparts. People infected
with HIV, for example, can avoid developing Aids by taking a
cocktail of antiviral drugs. But if they stop taking them, the
virus will rebound to its former level in a matter of weeks.
Patients have to take the drugs for the rest of their lives to
prevent the virus from wiping out their immune system.

Viruses mutate much faster than bacteria, so current antivirals
have a limited shelf life. And they all have a narrow scope of
attack. You might treat your flu with Tamiflu, but it won't cure
you of dengue fever or Japanese encephalitis. Scientists have to
develop antivirals one disease at a time -- a labour that can take
many years. As a result, we still have no antivirals for many of
the world's nastiest viruses.

Virologists are still waiting for their Penicillin Moment. But
they might not have to wait forever. Buoyed by advances in
molecular biology, a handful of researchers in labs around the US
and Canada are homing in on strategies that could eliminate not
just individual viruses, but any virus, wiping out viral infections
with the same efficiency that penicillin and ciproflaxacin bring to
the fight against bacteria. If these scientists succeed, future
generations may struggle to imagine a time when we were at the
mercy of viruses, just as we struggle to imagine a time before
antibiotics.

Three teams in particular are zeroing in on new antiviral
strategies, with each taking a different approach to the problem.
But at root they are all targeting our own physiology, the aspects
of our cell biology that allow viruses to take hold and reproduce.
If even one of these approaches pans out, we might be able to
eradicate any type of virus we want. Some day we might even be
faced with a question that today sounds absurd: are there viruses
that need protecting?

***

At 5am one day last autumn, in San Francisco's South of Market
district, Vishwanath Lingappa was making rabies soup. At his lab
station, he injected a syringe full of rabies virus proteins into a
warm flask loaded with other proteins, lipids, building blocks of
DNA, and various other molecules from ground-up cells. It cooked
for hours on Lingappa's bench, and occasionally he withdrew a few
drops to analyse its chemistry. By spinning the fluid in a
centrifuge, he could isolate small clumps of proteins that flew
towards the edge as the bigger ones stayed close to the centre.

To his mix, Lingappa had added a particular protein he wanted to
study. He suspected that the rabies virus used this protein in the infected cell to assemble
the capsid, or external shell, of replicated viruses. He tagged the
target protein with radioactive atoms, allowing him to follow it as
it interacted with other elements.

At 10am, Lingappa took pictures of the mixture. By lunchtime,
the images were ready to show to his staff. In the conference room,
a table was strewn with take-out sandwiches, and an abandoned bowl
of porridge sat on a sideboard. As Lingappa held up the films to
the light, his colleagues crowded behind him to make out black
streaks across the images.

As predicted, the tagged protein had joined with other proteins,
creating the microscopic machines that in a real infection would
assemble the rabies virus shell. Why would this matter? Because a
drug developed by Lingappa's firm, Prosetta Antiviral, has been
shown to interfere with this protein, blocking it from functioning
in these shell-making machines. If his gamble pays off, this is the
pathway by which an antiviral drug will stop cells from replicating
the rabies virus.

Lingappa came relatively late to his obsession with antivirals.
He trained as a cell biologist in the late 70s in the laboratory of
Günter Blobel, a Rockefeller University cell biologist who went on
to win the Nobel Prize in 1999. Blobel studied how cells work by
grinding them up and running experiments on their loose contents.
This type of cellular soup, known as a cell-free system, can
simulate the innerworkings of a cell, including the assembly of new genes and
proteins. By adjusting its composition -- leaving out a single
enzyme, for example -- scientists can figure out how a cell's
molecules work together to keep it alive. Under Blobel's tutelage,
Lingappa became a cellular chef de cuisine in his own right. For
example, he ran experiments to figure out how newly made proteins
were ferried through a cell to the place where they were needed.
After earning his PhD, Lingappa headed west to UC San Francisco to
continue his research.

He might have experimented his way to a quiet retirement had it
not been for his younger sister Jaisri, who was treating Aids
patients at the UCSF Medical Center. She spent a summer at
Rockefeller many years beforehand, at her brother's urging, and now
saw that cell-free systems might shed some light on viruses. At the
time, the prevailing dogma was that once a host cell made new virus
genes, the capsid could self-assemble around them. But Jaisri was
sceptical. She suspected that viruses needed help from host enzymes
to mould the shell into its proper shape. By experimenting in a
cell-free system, she reasoned, she might be able to identify those
host enzymes that the virus depended upon -- and figure out how to
block them. She asked her brother whether there was any chance her
idea could work. "I haven't a clue," Vishwanath replied. "Let's try
it."

The Lingappas began their experiments on hepatitis
B, a relatively simple virus that scientists already knew a great
deal about. They figured out how to get cell-free systems to
generate hepatitis B capsids. Next they tinkered with the soup's
recipe, taking out various enzymes and observing whether there was
any change to the shells it produced. Before long they had found
that a number of enzymes were essential to making the capsids. When
these enzymes were present, the cell-free system produced perfect
shells. Without them the system could manage only stunted,
half-formed shells.

They and their colleagues went on to run the same experiments on
HIV, and again found that the viruses needed lots of help. Host
enzymes had to join together to form complicated biological
machines with the right shape -- the right set of pockets, grooves
and clefts -- to grab parts of viruses and push them into their
proper place to build the shell. For each capsid-making machine,
the Lingappas reasoned, there should be a molecule they could lodge
in some key pocket, making it useless for hauling capsid proteins
into place. The machine would thereby be immobilised, and the
infected cell could no longer build viruses. By 2003, Vishwanath
had so much faith in his idea that he launched Prosetta.

The first thing researchers at Prosetta had to do was search for
promising candidates -- molecules of just the right shape to lodge
into the capsid-making machinery. They screened 80,000 compounds by
testing each in a cell-free system. Most couldn't stop capsids from
forming, but a few dozen did. Instead of focusing on one, Lingappa
decided to pursue almost all of them on the premise that a victory
against any one virus would help Prosetta extend its strategy to
all of them.

It was a gutsy strategy, and so far it's paying off. Studies --
in both cell cultures and on animals -- are showing that Prosetta's
approach can stop rabies, Ebola, influenza and a number of other
viruses. If, as Lingappa suspects, all viruses need help from their
host cells to assemble, he may have found a strategy that can work
against every virus that could ever make us sick.